Exaggerations in the cardiovascular responses to exercise in heart failure patients are mediated, in part, by an over active exercise pressor reflex (EPR). The EPR is a mechanism where blood pressure and heart rate increase in response to contraction-induced activation of primary afferent neurons and reflexive changes in autonomic outflow. Importantly, exaggerations in the EPR correlate with morbidity and mortality in heart failure patients. We developed a novel animal model to study the EPR in rats with heart failure. With this model, we have determined that the EPR is overactive in rats in heart failure just as it is in humans. We have also determined several mechanisms which contribute to this overactivity. First, we have determined that the TRPv1 receptor (previously known as the capsaicin receptor) mediates the EPR in the rat. Second, we have determined that, in spite of an exaggerated EPR, the group IV afferent neurons are less responsive to capsaicin in heart failure when compared to sham treated controls. Third, we have demonstrated that ablation of group IV afferent neurons (in non-cardiomyopathic animals) results in an overactive EPR similar to that observed in heart failure. Additionally, we have determined that group III afferent neurons maintain the EPR in the absence of group IV afferent responsiveness. Based on these collective findings, we hypothesize that reduced responsiveness in group IV afferent neurons leads to increased activation of group III afferent neurons and results in an overactive EPR in heart failure. To support this hypothesis, we have determined that the levels of nerve growth factor (NGF), which are essential to the maintenance of a majority of group IV afferent neurons is significantly decreased in skeletal muscle during heart failure. Importantly, NGF has recently been demonstrated to regulate cell surface expression of TRPv1 in primary afferent neurons. Though we observe no evidence of cell death in primary afferent neurons in heart failure, microarray data and western blot analyses reveal that transcripts and proteins that regulate cell surface expression of receptors are significantly down-regulated in heart failure. Furthermore, we demonstrate decreased cell surface expression of TRPv1 in dorsal root ganglia (DRG) in heart failure. Based on these data, we hypothesize that decreased cell surface expression of the TRPv1 receptor is critical to the development of the exaggerated EPR observed in heart failure. In these proposed studies, we will investigate the mechanisms by which this decreased surface expression occurs and we predict that an enhanced understanding of the mechanisms regulating this process will provide novel targets for the treatment of the exaggerated EPR in individuals with heart failure.